A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect

Sai-Nan Liu; Jia-Hui Meng; Li-Yun Cui; Hua Chen; Lin-Qi Shi; Ru-Jiang Ma

doi:10.1007/s10118-024-3090-z

Your Location：

Home >

Browse articles >

A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect

RESEARCH ARTICLE | Updated：2024-04-12

- A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect
- A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect
- 高分子科学（英文版） 2024年42卷第5期页码：559-569
- Affiliations：
  
  a.Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, Tianjin Key Laboratory of Functional Polymer Materials, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
  b.Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300192, China
- Author bio：
  
  shilinqi@nankai.edu.cn (L.Q.S.)
  marujiang@nankai.edu.cn (R.J.M.)
- Funds：
  
  This work was financially supported by the National Key R&D Program of China (Nos. 2022YFA1205703 and 2022YFA1205702), the National Natural Science Foundation of China (Nos. 51773099, 51933006 and 52103183) and Haihe Laboratory of Sustainable Chemical Transformations (No. YYJC202102).;Electronic supplementary information (ESI) is available free of charge in the online version of this article at http://doi.org/10.1007/s10118-024-3090-z.
- DOI：10.1007/s10118-024-3090-z
  中图分类号：
- 纸质出版日期：2024-5-1，
  
  网络出版日期：2024-2-28，
  
  收稿日期：2023-11-25，
  
  修回日期：2023-12-26，
  
  录用日期：2023-12-27
Scan for full text
Liu, S. N.; Meng, J. H.; Cui, L. Y.; Chen, H.; Shi, L. Q.; Ma, R. J. A dynamic covalent bonding-based nanoplatform for intracellular co-delivery of protein drugs and chemotherapeutics with enhanced anti-cancer effect. Chinese J. Polym. Sci. 2024, 42, 559–569

Sai-Nan Liu, Jia-Hui Meng, Li-Yun Cui, et al. A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect[J]. Chinese Journal of Polymer Science, 2024,42(5):559-569.
Liu, S. N.; Meng, J. H.; Cui, L. Y.; Chen, H.; Shi, L. Q.; Ma, R. J. A dynamic covalent bonding-based nanoplatform for intracellular co-delivery of protein drugs and chemotherapeutics with enhanced anti-cancer effect. Chinese J. Polym. Sci. 2024, 42, 559–569 DOI： 10.1007/s10118-024-3090-z.

Sai-Nan Liu, Jia-Hui Meng, Li-Yun Cui, et al. A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect[J]. Chinese Journal of Polymer Science, 2024,42(5):559-569. DOI： 10.1007/s10118-024-3090-z.

摘要

A well-designed intracellular RNase A and DOX co-delivery system based on dynamic covalent bond was prepared with good stability and satisfied LC/EE under physiological conditions. This nanoplatform showed a synergistic and enhanced antic-cancer effect and may promote the development of anticancer combination therapy.

Abstract

Efficient intracellular delivery of protein drugs is critical for protein therapy. The combination of protein drugs with chemotherapeutics represents a promising strategy in enhancing anti-cancer effect. However

co-delivery systems for efficient delivery of these two kinds of drugs are still lacking because of their different properties. Herein

we show a well-designed delivery system based on dynamic covalent bond for efficient intracellular co-delivery of ribonuclease A (RNase A) and doxorubicin (DOX). Two polymers

PEG-

-P(Asp-

-AspDA) and PAE-

-P(Asp-

-AspPBA)

and two 2-acetylphenylboronic acid (2-APBA)-functionalized drugs

2-APBA-RNase A and 2-APBA-DOX

self-assemble into mixed-shell nanoparticles (RNase A/DOX@MNPs)

via

dynamic phenylboronic acid (PBA)-catechol bond between PBA and dopamine (DA) moieties. The PBA-catechol bond endows the nanoparticles with high stability and excellent stimulus-responsive drug release behavior. Under the slight acidic environment at tumor tissue

RNase A/DOX@MNPs are positively charged

promoting their endocytosis. Upon cellular uptake into endosome

further protonation of PAE chains leads to the rupture of endosomes because of the proton sponge effect and the cleavage of PBA-catechol bond promotes the release of two drugs. In cytoplasm

the high level of GSH removed the modification of 2-APBA on drugs. The restored RNase A and DOX show a synergistic and enhanced antic-cancer effect. This system may be a promising platform for intracellular co-delivery of protein drugs and chemotherapeutics.

关键词

Keywords

Drug co-deliveryCombination therapyDynamic covalent bond

references

Chung, J. E.; Tan, S.; Gao, S. J.; Yongvongsoontorn, N.; Kim, S. H.; Lee, J. H.; Choi, H. S.; Yano, H.; Zhuo, L.; Kurisawa, M.; Ying, J. Y. Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy.Nat. Nanotechnol.2014, 9, 907−912..

Leader, B.; Baca, Q. J.; Golan, D. E. Protein therapeutics: a summary and pharmacological classification.Nat. Rev. Drug Discov.2008, 7, 21−39..

Vermonden, T.; Censi, R.; Hennink, W. E. Hydrogels for protein delivery.Chem. Rev.2012, 112, 2853−2888..

Yang, Z. C.; Li, Y. C.; Li, F.; Huang, Q. R.; Zhang, G.; Shi, T. F. Design and preparation of pH-responsive curdlan hydrogels as a novel protein delivery vector.Chinese J. Polym. Sci.2016, 34, 280−287..

Stewart, M. P.; Langer, R.; Jensen, K. F. Intracellular delivery by membrane disruption: mechanisms, strategies, and concepts.Chem. Rev.2018, 118, 7409−7531..

Fu, L. Y.; Hua, X. W.; Jiang, X. Y.; Shi, J. J. Multistage systemic and cytosolic protein delivery for effective cancer treatment.Nano Lett.2022, 22, 111−118..

Nischan, N.; Herce, H. D.; Natale, F.; Bohlke, N.; Budisa, N.; Cardoso, M. C.; Hackenberger, C. P. R. Covalent attachment of cyclic TAT peptides to GFP results in protein delivery into live cells with immediate bioavailability.Angew. Chem. Int. Ed.2015, 54, 1950−1953..

Antonio, J. P. M.; Russo, R.; Carvalho, C. P.; Cal, P. M. S. D.; Gois, P. M. P. Boronic acids as building blocks for the construction of therapeutically useful bioconjugates.Chem. Soc. Rev.2019, 48, 3513−3536..

Qin, X. F.; Yu, C. M.; Wei, J.; Li, L.; Zhang, C. W.; Wu, Q.; Liu, J. H.; Yao, S. Q.; Huang, W. Rational design of nanocarriers for intracellular protein delivery.Adv. Mater.2019, 31, 1902791..

Dutta, K.; Hu, D.; Zhao, B.; Ribbe, A. E.; Zhuang, J. M.; Thayumanavan, S. Templated self-assembly of a covalent polymer network for intracellular protein delivery and traceless release.J. Am. Chem. Soc.2017, 139, 5676−5679..

Ren, L. F.; Lv, J.; Wang, H.; Cheng, Y. Y. A coordinative dendrimer achieves excellent efficiency in cytosolic protein and peptide delivery.Angew. Chem. Int. Ed.2020, 59, 4711−4719..

Kretzmann, J. A.; Luther, D. C.; Evans, C. W.; Jeon, T.; Jerome, W.; Gopalakrishnan, S.; Lee, Y.; Norret, M.; Iyer, K. S.; Rotello, V. M. Regulation of proteins to the cytosol using delivery systems with engineered polymer architecture.J. Am. Chem. Soc.2021, 143, 4758−4765..

Scaletti, F.; Hardie, J.; Lee, Y. W.; Luther, D. C.; Ray, M.; Rotello, V. M. Protein delivery into cells using inorganic nanoparticle-protein supramolecular assemblies.Chem. Soc. Rev.2018, 47, 3421−3432..

He, C. L.; Tang, Z. H.; Tian, H. Y.; Chen, X. S. Co-delivery of chemotherapeutics and proteins for synergistic therapy.Adv. Drug Deliv. Rev.2016, 98, 64−76..

Rubinfeld, B.; Upadhyay, A.; Clark, S. L.; Fong, S. E.; Smith, V.; Koeppen, H.; Ross, S.; Polakis, P. Identification and immunotherapeutic targeting of antigens induced by chemotherapy.Nat. Biotechnol.2006, 24, 205−209..

Giantonio, B. J.; Catalano, P. J.; Meropol, N. J.; O'Dwyer, P. J.; Mitchell, E. P.; Alberts, S. R.; Schwartz, M. A.; Benson, A. B. I. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the eastern cooperative oncology group study E3200.J. Clin. Oncol.2007, 25, 1539−1544..

Kim, C. S.; Mout, R.; Zhao, Y. L.; Yeh, Y.; Tang, R.; Jeong, Y.; Duncan, B.; Hardy, J. A.; Rotello, V. M. Co-delivery of protein and small molecule therapeutics using nanoparticle-stabilized nanocapsules.Bioconjugate Chem.2015, 26, 950−954..

Phua, S. Z. F.; Yang, G. B.; Lim, W. Q.; Verma, A.; Chen, H. Z.; Thanabalu, T.; Zhao, Y. L. Catalase-integrated hyaluronic acid as nanocarriers for enhanced photodynamic therapy in solid tumor.ACS Nano2019, 13, 4742−4751..

Ng, D. Y. W.; Arzt, M.; Wu, Y. Z.; Kuan, S. L.; Lamla, M.; Weil, T. J. Constructing hybrid protein zymogens through protective dendritic assembly.Angew. Chem. Int. Ed.2014, 53, 324−328..

Sangsuwan, R.; Tachachartvanich, P.; Francis, M. B. Cytosolic delivery of proteins using amphiphilic polymers with 2-pyridinecarboxaldehyde groups for site-selective attachment.J. Am. Chem. Soc.2019, 141, 2376−2383..

Liu, C. Y.; Wan, T.; Wang, H.; Zhang, S.; Ping, Y.; Cheng, Y. Y. A boronic acid-rich dendrimer with robust and unprecedented efficiency for cytosolic protein delivery and CRISPR-Cas9 gene editing.Sci. Adv.2019, 5, eaaw8992..

Huang, S.; Kong, X.; Xiong, Y. S.; Zhang, X. R.; Chen, H.; Jiang, W. Q.; Niu, Y. Z.; Xu, W. L.; Ren, C. G. An overview of dynamic covalent bonds in polymer material and their applications.Eur. Polym. J.2020, 141, 110094..

Chakma, P.; Konkolewicz, D. Dynamic covalent bonds in polymeric materials.Angew. Chem. Int. Ed.2019, 58, 9682−9695..

Chen, H.; Cui, L. Y.; Li, Y. F.; Liu, Y.; Ma, R. J.; Shi, L. Q. Phenylboronic acid functionalized polymer nanocarriers for intracellular delivery of protein drugs.Acta Polymerica Sinica (in Chinese)2023, 54, 451−466..

Zhou, Y.; Zhai, Z. H.; Yao, Y. M.; Stant, J. C.; Landrum, S. L.; Bortner, M. J.; Frazier, C. E.; Edgar, K. J. Oxidized hydroxypropyl cellulose/carboxymethyl chitosan hydrogels permit pH-responsive, targeted drug release.Carbohydr. Polym.2023, 300, 120213..

Liu, C. Y.; Shen, W. W.; Li, B. N.; Li, T. F.; Chang, H.; Cheng, Y. Y. Natural polyphenols augment cytosolic protein delivery by a functional polymer.Chem. Mater.2019, 31, 1956−1965..

Su, S.; Wang, Y. Y.; Du, F. S.; Lu, H.; Li, Z. C. Dynamic covalent bond-assisted programmed and traceless protein release: high loading nanogel for systemic and cytosolic delivery.Adv. Funct. Mater.2018, 28, 1805287..

Cal, P. M. S. D.; Vicente, J. B.; Pires, E.; Coelho, A. V.; Veiros, L. F.; Cordeiro, C.; Gois, P. M. P. Iminoboronates: a new strategy for reversible protein modification.J. Am. Chem. Soc.2012, 134, 10299−10305..

Ding, X. Y.; Li, G.; Zhang, P.; Jin, E.; Xiao, C. S.; Chen, X. S. Injectable self-healing hydrogel wound dressing with cysteine-specific on-demand dissolution property based on tandem dynamic covalent bonds.Adv. Funct. Mater.2021, 31, 2011230..

Chen, D. Y.; Jin, Z. K.; Zhao, B.; Wang, Y. S.; He, Q. J. MBene as a theranostic nanoplatform for photocontrolled intratumoral retention and drug release.Adv. Mater.2021, 33, 2008089..

Springsteen, G.; Wang, B. H. Alizarin red S. as a general optical reporter for studying the binding of boronic acids with carbohydrates.Chem. Commun.2001, 58, 1608−1609..

Ma, R. J.; Wang, B. L.; Sun, P. C.; Shi, L. Q.11B 3Q MAS NMR study on glucose-responsive micelles self-assembled from PEG- b-P(AA- co-AAPBA).Chin. J. Chem2014, 32, 97−102..

Ren, J.; Zhang, Y. X.; Zhang, J.; Gao, H. J.; Liu, G.; Ma, R. J.; An, Y. G.; Kong, D.; Shi, L. Q. pH/Sugar dual responsive core-cross-linked PIC micelles for enhanced intracellular protein delivery.Biomacromolecules2013, 14, 3434−3443..

Zhang, Y. X.; Fu, H.; Chen, J. J.; Xu, L. L.; An, Y. L.; Ma, R. J.; Zhu, C. L.; Liu, Y.; Ma, F. H.; Shi, L. Q. Holdase/foldase mimetic nanochaperone improves antibody-based cancer immunotherapy.Small Methods2022, 7, 2201051..

Cheng, T. J.; Zhang, Y. M.; Liu, J. J.; Ding, Y. X.; Ou, H. L.; Huang, F.; An, Y. G.; Liu, Y.; Liu, J. F.; Shi, L. Q. Ligand-switchable micellar nanocarriers for prolonging circulation time and enhancing targeting efficiency.ACS Appl. Mater. Interfaces2018, 10, 5296−5304..

Yan, M.; Du, J. J.; Gu, Z.; Liang, M.; Hu, Y. F.; Zhang, W. J.; Priceman, S.; Wu, L.; Zhou, Z. H.; Liu, Z.; Segura, T.; Tang, Y.; Lu, Y. F. A novel intracellular protein delivery platform based on single-protein nanocapsules.Nat. Nanotechnol.2010, 5, 48−53..

Cui, L. Y.; Liu, S. N.; Wu, F.; Chen, H.; Li, Y. F.; Shi, L. Q.; Liu, Y.; Ma, R. J. Protein@PP-Zn nanocomplex assembled by coordination of zinc ions used for intracellular protein delivery.Sci. China Chem.2023, 66, 2354−2362..

Mosquera, J.; Garcia, I.; Liz-Marzan, L. M. Cellular uptake of nanoparticles versus small molecules: a matter of size.Acc. Chem. Res.2018, 51, 2305−2313..

Ruan, L. F.; Chen, J.; Du, C. C.; Lu, H. R.; Zhang, J. Y.; Cai, X. M.; Dou, R.; Lin, W. C.; Chai, Z. F.; Nie, G. J.; Hu, Y. Mitochondrial temperature-responsive drug delivery reverses drug resistance in lung cancer.Bioact. Mater.2022, 13, 191−199..

Ye, M. Z.; Han, Y. X.; Tang, J. B.; Piao, Y.; Liu, X. R.; Zhou, Z. X.; Gao, J. Q.; Rao, J. H.; Shen, Y. Q. A tumor-specific cascade amplification drug release nanoparticle for overcoming multidrug resistance in cancers.Adv. Mater.2017, 29, 1702342..

More>

浏览量

Downloads

CSCD

文章被引用时，请邮件提醒。

Submit

工具集

关联资源

PLG-g-mPEG Mediated Multifunctional Nanoparticles for Photoacoustic Imaging Guided Combined Chemo/Photothermal Antitumor Therapy

“Solid-Liquid” Vitrimers Based on Dynamic Boronic Ester Networks

Co-delivery of Doxorubicin and Afatinib with pH-responsive Polymeric Nanovesicle for Enhanced Lung Cancer Therapy